Project Summary/Abstract Magnetic Resonance Imaging or MRI is a powerful tool for both clinical and research applications, used to non-invasively map tissues and organs in the body for both diagnosis and treatment. Contrast agents serve an important role in enhancing the sensitivity, providing greater detail and higher spatial resolution. The commercially used contrast agents are based on gadolinium because of the positive (brightening or T1) type enhancement, but for patients with renal issues (including a large proportion of patients over 60) gadolinium is not recommended because of its association with nephrogenic systemic fibrosis. This is a severe condition resulting from fibrosis of skin, internal organs, and joints. There is a strong demand for contrast agents that have the kind of positive contrast ability as gadolinium without lanthanide metals. For pre-clinical studies, it is desirable to have a contrast agent in nanostructured form with controllable diameters, homogeneous metal content, with positive contrast. We have recently demonstrated that the manganese-iron oxo cluster, with stoichiometry Mn8Fe4(L)16 (L = vinyl benzoic acid) when co-polymerized with polystyrene has significantly improved relaxivity properties. Compared with the cluster alone, the r2 decreased while the r1 is enhanced, converting the cluster from a negative to positive contrast agent. This prototype has been thoroughly characterized and found to be stable under a variety of pH, BSA, PBS, FBS, human serum, and cell environments. Here we propose to: 1) Determine the biocompatibility of Mn8Fe4 with 4 nanocarriers: hydrophobic polystyrene, hydrophilic polyacrylamide, porous silica with hexagonally packed pores (MCM-41) or radially oriented pores (MSNs) with a specific set of surface groups (polyethylene glycol, folate), 2) Increase sensitivity by developing algorithms that can combine both T1 and T2 weighted data to lead to higher sensitivity, better resolution, and remove misleading artifacts from MRI images, 3) Investigate new Manganese oxo clusters for ultra high relaxivity. We believe the cluster-nanocarrier system has the potential to provide an alternative to gadolinium contrast agents for patient likely to be intolerant of the lanthanide. We believe that magnetic coupling within the clusters improves relaxivity of the metal, and that the nanocarrier provides both the possibility for enhancement and increased biostability. The objective is to design a safe, biocompatible material that has strong relaxivity properties.